Hydrogel co-polymer composition and its uses, for example as a wound dressing

ABSTRACT

The present invention provides a hydrogel composition, preferably for the treatment of wounds, comprising a hydrophilic co-polymer carrying multiple pendant anionic groups, wherein the polymer is derived from a first monomer and a second monomer, wherein both monomers have an octanohwater partition coefficient Log P value of less than 0, and, the Log P value of the first monomer is greater (more positive) than the second monomer. Preferably the difference between the Log P value for the two monomers is at least 0.1, preferably at least 0.2. The difference between the Log P value for the two monomers is preferably less than 2. The weight ratio (w/w) of the first monomer/second monomer in the hydrogel composition is preferably equal to or more than about 1. The pendant anionic groups may be sulphonyl groups, e.g. sulphonic acid groups or salts thereof. The anionic group in both first and second monomers may be in salt form and the counterion for both monomers is preferably the same.

FIELD OF THE INVENTION

The present invention relates to a hydrogel co-polymer composition andits uses, particularly those including use as a wound dressing, and forthe treatment of pain and/or inflammation.

The present invention develops the concept of “Pro-Ionic™” treatment ofwounds introduced in our PCT patent application No. PCT/GB2006/002632(publication no. WO/2007007115), the contents of which are incorporatedherein by reference, in which a hydrogel dressing in contact with thewound provides in use a controlled-moisture environment for the woundand selective uptake of proteins and ions from the wound, to stimulateand/or maintain the wound healing process.

More particularly, according to the present invention the hydrogel hassurprisingly been found to modulate the activity and or concentration ofproteins in biological environments, for example in skin lesions,particularly chronic ulcerous skin lesions, which is believed to assistin the healing process of an affected area and/or have one or more ofthe beneficial effects mentioned below.

Without wishing to be bound by theory, the hydrogel is believed to mimicthe function of natural glycosminoglycans of a normal healing wound, andin particular certain sulphonated glycosaminoglycans of theextracellular matrix such as heparin, using a moist wound healingenvironment where the water levels are controlled to avoid thedisadvantages of too much or too little moisture. In particular it isbelieved that the hydrogel comprising two or more structurally differentmultiple strongly hydrophilic pendant anionic groups counter balanced byone or more cations mimic some of the functions of the structurallydifferent strongly hydrophilic groups found in naturalglycosoaminoglycans and in particular certain sulphonatedglycosaminoglycans such as heparin. In the case of chronic wounds, thehydrogel suppresses the inflammation processes that are associatedchronic failure of the wound to heal and thus stimulates and/ormaintains the normal healing process. In the case of acute wounds, thedressing suppresses a tendency towards chronic failure to heal, andstimulates and/or maintains the normal healing process.

The hydrogel used is a certain type of hydrous hydrophilic (ionic)polymer, described in more detail below. The ions covalently linked tothe polymer molecule are generally anions; the cations are generallypresent as counterions (generally mono- or di-valent cations such asmetal ions or primary or substituted ammonium ions). The hydrogel,including its associated water and ions, may have one or more, forexample simultaneously any two or more, of the following beneficialeffects, without the need for other specific bioactive agents, namely:(1) reduction in inflammation and/or the healing of a wound, (2) reducedwound odour, (3) beneficial wound debridement, (4) beneficial skinconditioning, (5) beneficial pain relief, and (6) in combination,beneficial suppression of the processes which lead to, and/or maintain,a chronic wound with beneficial wound bed stimulation and/or maintenanceof the healing process (see also WO2007/007115). Preferably, thebeneficial effects on the wound include simultaneously one or more, morepreferably two or more, more preferably three or all, of effects (1) to(6).

BACKGROUND OF THE INVENTION Lesion Healing Process

The normal process of healing of a skin lesion (wound) typicallyproceeds via four distinct sequential stages or phases, namelyhaemostasis, inflammation, proliferation and maturation.

Haemostasis is the vascular response stage, occurring immediately afterthe insult is suffered, and normally lasts for up to about three days inhumans. The wound may bleed initially, and the blood then clots.

Inflammation normally arises about one day after the insult, andtypically continues until about six days after the insult. Inflammationinvolves one or more of redness, heat, swelling and pain. The woundstarts to exude fluid, which serves to remove debris, and proteases arereleased into the wound area. White blood cells and macrophages begin tocongregate in the lesion zone, the former to clear debris and the latterfor phagocytosis and to release growth factors to stimulate fibroblasts.During this phase the extracellular matrix is constructed.

Proliferation normally arises about four days after the insult, andtypically continues until about 21 days after the insult, and involvesthe gradual formation of granulation tissue to fill the lesion zone. Theredness, heat, swelling and pain gradually subside during this phase.For these reasons, granulation and contracture are sometimes identifiedas sub-phases within the proliferation phase. During proliferation, themacrophages stimulate vascular endothelial growth factor (VEGF) tostimulate new blood vessel growth, and the concentration of fibroblastsincrease, producing collagen for the new tissues.

The maturation phase normally arises about 21 days after the insult, andtypically continues for several weeks, months or even years thereafter.Maturation involves contraction of the wound, growth of new epithelialtissue covering the wound, and possibly scar formation. During thisphase myofibroblasts develop from the fibroblasts and the collagenfibres gradually mature and become relatively more organised.

Generally, different parts of a wound heal at different rates, so thatit is common for some parts of a normal wound to be at a more advancedstage of healing than others.

The above timescale of a normal wound is provided for generalillustration only, and is not definitive for all normal wound healing.The present invention is not limited by any requirement that the normalwound healing process must follow any particular pathway or timescale.

Chronic Ulcerous Skin Lesions

Chronic skin lesions arise when a skin wound generally fails to followan appropriate timely healing process to achieve the normal sustainedand stable anatomic and functional integrity of the healed tissue.Generally speaking, a skin lesion which has failed to make at leastsubstantial progress towards healing within a period of at least aboutthree months, or which has become stable in a partially healed state formore than about three months, could be categorised as chronic, althougheven this general guide is not an absolute marker as the age and fitnessof the patient, as well as other factors such as diseases or disorderssuffered by the patient (for example, circulatory disorders), cansignificantly lengthen the normal healing process. A skin lesion whichis unhealed after at least about one month, for example after at leastabout six months, can be categorised as chronic.

A chronic skin lesion is ulcerous where it involves focal loss of theepidermis and at least part of the dermis.

Malignant or pre-malignant chronic ulcerous skin lesions may arise inconnection with a primary cancer of the skin, or with a metastasis tothe skin from a local tumour or from a tumour in a distant site. Theymay be draining or non-draining. They may, for example, take the form ofa cavity, an open area on the surface of the skin, skin nodules, or anodular growth extending from the surface of the skin.

Benign chronic ulcerous skin lesions are not associated with cancer, andinclude venous leg ulcers, venous foot ulcers, arterial leg ulcers,arterial foot ulcers, decubitus ulcers (e.g. pressure sores, bedsores),post-surgical ulcerous lesions and chronic burn lesions. They may, forexample, take the form of a cavity, an open area on the surface of theskin, skin nodules, or a nodular growth extending from the surface ofthe skin. Typically, they comprise an open granulating area on thesurface of the skin.

Chronic ulcerous skin lesions are usually accompanied by other chronicsymptoms apart from the failure of the normal healing process. Typicalaccompanying chronic symptoms include one or more of pain, exudation,malodour, excoriation, spreading of the wound, tissue necrosis,irritation and hyperkeratosis. Such symptoms can be extremelydebilitating and embarrassing for patients, and can seriously harm thepatient's quality of life. In severe cases, they can require amputationof limbs or even death.

Chronic ulcerous skin lesions can also be categorised according to theirexudation. General categorisation is into the three categories “highexudation”, “medium exudation” and “low exudation”. Exudate managementis a particularly difficult task for the caring professional attendingto the patient. A balance needs to be struck between the desire toremove exudate to maintain the patient's quality of life at as high alevel as possible, and maintenance of an appropriate level of fluid toprevent the lesion becoming too dry or too wet.

The Role of Inflammation and the Complement Cascade

The complement cascade during inflammation is part of the body's defenceagainst invading microorganisms during the wound healing process. Thecomplement cascade includes the formation of natural antimicrobials suchas opsonins (C3b), chemotactic factors for neutrophils and mononuclearphagocytes (C5a) as well as anaphylatoxins (C5a, C3a).

The complement cascade is thus implicated with the general inflammationresponse in the underlying failure of chronic wounds to progress.

The kinin cascade leads to the production of bradykinin, which isimplicated in the pain response.

Therefore, treatment of a patient to inhibit inflammation and/or thecomplement cascade and/or the kinin cascade, as well as other mechanismsinvolved in the early stages of wound healing, will be expected toassist in causing a chronic wound to start healing, and in preventing anacute wound from becoming chronic, and in the reduction of associatedpain.

PRIOR ART TREATMENTS

WO-A-00/07638, the contents of which are incorporated herein byreference, discloses bioadhesive hydrogel compositions and their use inwound dressings. The polymer composition is stated to preferablycomprise also a non-hydrophilic (hydrophobic) polymer, and may comprisea specifically antimicrobial agent such as citric acid or stannouschloride. No information is given as to any effects of the hydrogelcompositions on the proteases of wounds, for example human skin wounds.More generally, there is no teaching that the polymer per se in thehydrogel, including its associated water and ions, provides anyinhibition of inflammation or the complement cascade alone or incombination with the additional beneficial effects on the woundmentioned as (1) to (5) above, without the need for other bioactiveagents.

It is known to apply dressings to chronic skin lesions, with the aim ofpromoting their healing. Examples of such prior art dressings forchronic ulcerous skin lesions include Aquacel™ (ConvaTec)(http://www.dressings.org/Dressings/aquacel.html), Intrasite™ (Smith &Nephew) (http://www.dressings.org/Dressings/intrasit.gel.html) andAvance™ (Medlock Medical)(http://www.medlockmedical.com/woundcare/avance.htm).

Generally speaking, and without commenting specifically on theparticular examples given above, prior art dressings for chroniculcerous skin lesions suffer from a variety of problems. For example,they can cause maceration of peri-wound areas, they can absorb woundexudate only partially, they can cause contact dermatitis, varicoseeczema or skin stripping (e.g. due to aggressive or allergenic adhesivematerials). Furthermore, even in cases where the prior art dressings forchronic skin lesions contribute to successful healing, scarring of thehealed wound and poor quality of healed tissue can often be found.

The prior art dressings for chronic ulcerous skin lesions can also beslow and difficult to apply and change, and require frequent changing.Many patients experience considerable—sometimes unbearable—painassociated with changing of the dressing, over and above the oftenconsiderable general pain associated with the lesion itself. The use ofopiate painkillers to deal with this pain can lead to opiate dependencyand addiction.

Prior art dressings that require frequent changing cause a significantincrease in costs to healthcare services and providers, as a nurse orother healthcare professional needs to attend the patientcorrespondingly more often. In addition, the material costs of thedressings clearly are higher because of the frequent application offresh dressings.

Specific anti-inflammatory chemical agents are well known. However, theyare relatively expensive speciality chemicals and their addition tonormal or normalising wounds can do more harm than good. In addition,they do not overcome the problem of pain and the other problems of thedressings themselves.

In an article entitled “A small study in healing rates and symptomcontrol using a new sheet hydrogel dressing” in Journal of Wound Care,July 2004, 13(7), and in a poster presentation at the Tissue ViabilitySociety (TVS) Conference in Torquay, UK, in April 2003, available onhttp://www.activahealthcare.co.uk/pdf/cs-actiformcool2.pdf, the contentsof all of which are incorporated herein by reference, Sylvie Hamptondescribed a study into the effects of a sheet hydrogel dressing onchronic leg and foot ulcers of at least six months duration (average 9months to two years) in 16 human patients. The pre-treatment ulcers ofalmost all of the patients were either high exudation or mediumexudation. The sheet hydrogel dressing was supplied by Activa Healthcareof Burton-upon-Trent, UK (tel: +44 8450 606 707; web:www.activahealthcare.co.uk) under the name ActiFormCool™.

The results published by Sylvie Hampton showed the potential forsubstantial advantages deriving from the use of ActiFormCool™ as adressing in the treatment of chronic leg and foot ulcers. However,neither the Journal of Wound Care article nor the poster presentationmentioned above disclosed the underlying nature of the therapeuticeffect or the nature of any active component of the composition ofActiFormCool™. More generally, there was no teaching that the polymerper se in the hydrogel, including its associated water and ions,provides any specific or controlled interaction with proteins.

There is also no teaching that anionic polymers used for wound dressingsneed to combine both the correct balance of pendant anionic group withthe appropriate counter cation in order to contro interactions withproteins.

WO2007/007115, the contents of which are incorporated herein byreference, discloses the use of certain hydrogel compositions in thetreatment of, inter alia, chronic ulcerous skin lesions. It discloseshydrogel compositions in the Examples derived from2-acrylamido-2-methylpropane sulphonic acid (commonly known as NaAMPS)and, in some cases NaAMPS (as the major component) and the potassiumsalt of 2-acrylamido-2-methylpropane sulphonic acid (commonly known asSPAK) as the minor component).

WO 00/45864 discloses hydrogel bioadhesive compositions, which may beused in wound dressings. The hydrogel compositions may be formed fromNaAMPS and SPAK. It states in this document that “where the ionic watersoluble monomer comprises a mixture of NaAMPS and SPA or one of itssalts, it is generally preferred that a high ratio of NaAMPS to SPA, forexample 70:30 and above, is used”.

Basis of the Present Invention

The present invention is based on our surprising finding that thehydrogels described below exhibit specific interactions with proteins,particularly fibrinogen. The hydrogel compositions have been found to beparticularly suitable for use as wound dressings and/or for theinhibition of inflammation. Furthermore, we believe that, in use, thedressing is a self-regulating system, whereby the extent of inhibitionof inflammation and/or the complement cascade and/or the kinin cascadecan reduce as the wound approaches a normalised state, so thatundesirable levels of inhibition of these responses are not found inpractice. Furthermore, this self-regulation is exhibited by freshdressings newly applied in dressing-changes, so that it appears that thehydrogel system responds sensitively to the state of healing of thewound.

It is believed that the hydrogels of the present invention may moreclosely mimic certain natural glycosminoglycans such as heparin than thehydrogels disclosed in PCT/GB2006/002632 (WO2007/007115). In particular,it is believed that they may more closely mimic the properties ofheparin and other glycosaminoglycans that can lead to one or more of (i)improved wound healing, (ii) reduction in inflammation, (iii) inhibitionof the complement cascade and (iv) inhibition of the kinin cascade.

BRIEF DESCRIPTION OF THE INVENTION

According to a first aspect, the present invention provides a hydrogelcomposition, preferably for the treatment of wounds, comprising ahydrophilic co-polymer carrying multiple pendant anionic groups, whereinthe polymer is derived from a first monomer and a second monomer,wherein both monomers have an octanol:water partition coefficient Log Pvalue of less than 0, and, the Log P value of the first monomer isgreater (more positive) than the second monomer, preferably thedifference between the Log P value for the two monomers is at leastabout 0.1, preferably at least about 0.2. The difference between the LogP value for the two monomers is preferably less than about 2. The firstand second monomers may be any monomers suitable for producing ahydrogel composition, and include, but are not limited to the monomersdisclosed herein. The pendant anionic groups may be sulphonyl groups,e.g. sulphonic acid groups or salts thereof.

The first monomer may have an octanol:water partition coefficient Log Pvalue greater than the second monomer. Preferably, the weight ratio(w/w) of the first monomer/second monomer in the hydrogel composition isequal to or more than about 1.

Accordingly to a second aspect, the present invention provides ahydrogel composition, preferably for the treatment of wounds, comprisinga hydrophilic copolymer formed from a first monomer and a secondmonomer, wherein the first monomer comprises an olefinically unsaturatedsulphonic acid monomer or salt thereof, preferably an acrylic acid estersulphonic acid monomer or salt thereof, and the second monomer comprisesan olefinically unsaturated sulphonic acid monomer or salt thereof,different from the first monomer and preferably an acrylamide sulphonicacid monomer or salt thereof, the weight ratio (w/w) of the firstmonomer/second monomer in the hydrogel is equal to or more than about 1and, either (i) the sulphonic group in both first and second monomers isin acidic form or (ii) the sulphonic group in both first and secondmonomers is in salt form and the counterion for both monomers is thesame. The hydrophilic polymer in the second aspect preferably hasmultiple pendant anionic groups, preferably multiple pendant sulphonylgroups. Preferably, both monomers have an octanol:water partitioncoefficient Log P value less than 0, and the first monomer has a Log Pvalue greater than (more positive than) than the second monomer.

Preferably, both first and second monomers are salts of olefinicallyunsaturated sulphonic acid monomers. Preferably, the counterion for bothsalts is the same, preferably sodium. Preferably, both first and secondmonomers have an octanol:water partition coefficient Log P value of lessthan 0, and the difference between Log P for the two monomers is atleast about 0.1, preferably at least about 0.2. The difference betweenLog P between the two monomers is preferably less than about 1.

Reference to the “hydrogel composition of the present invention” hereinshall be synonymous with “the hydrogel composition of the first aspectof the invention and/or the hydrogel composition of the second aspect ofthe invention”.

The present invention further provides a method of treating a wound in ahuman or non-human mammal, particularly a human, comprising contactingthe wound for an effective period of time with a hydrogel composition ofthe present invention.

The present invention further provides the use of a hydrogel compositionof the present invention in the preparation of a topical medicament forthe treatment of a wound, for example a chronic skin lesion, in a humanor non-human mammal, particularly a human.

The hydrogel composition of the present invention may be for thetreatment of a wound, for example a chronic skin lesion, in a human ornon-human mammal, particularly a human.

The wound may be a skin wound. The wound may be a chronic ulcerous skinlesion. The chronic ulcerous skin lesion may be selected from venous legulcers, venous foot ulcers, arterial leg ulcers, arterial foot ulcers,decubitus ulcers (e.g. pressure sores, bedsores), post-surgical ulcerouslesions and chronic burn lesions.

The method of the present invention may comprise the contacting of thewound with the hydrogel composition of the present invention for aneffective period of time to promote healing with simultaneous reductionin one or more of pain, exudation, malodour, excoriation, spreading ofthe wound, tissue necrosis, irritation and hyperkeratosis.

The present invention further provides a method of treating skin-derivedor tissue-derived pain in a human or non-human mammal, particularly ahuman, by applying to the painful area as a topical dressing a hydrogelcomposition of the present invention.

The present invention further provides a method of inhibitinginflammation and/or the complement cascade and/or the kinin cascade in ahuman or non-human animal patient, comprising contacting an affectedlocation of the patient's body for an effective period of time with ahydrogel composition of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 to 3 show results from the Examples below, and in particular:

FIG. 1 shows the results of Table 1 below in a graph of retention time(mins) versus Log 10 molecular weight for various molecules in a gelpermeation chromatography experiment detailed below;

FIG. 2 shows the results of Table 2 below in a graph of peak area(units) versus fibrinogen concentration (g/ml); and

FIG. 3 shows the results from Table 6 below in a chart of fibrinogenconcentration in supernatant fluid (g/100 ml) after 22 hrs exposure tosix different hydrogels of Examples 1 to 6.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, the present invention provides a hydrogelcomposition, preferably for the treatment of wounds, comprising ahydrophilic co-polymer carrying multiple pendant anionic groups, whereinthe polymer is derived from a first monomer and a second monomer,wherein both monomers have an octanol:water partition coefficient Log Pvalue of less than 0, and the difference between the Log P value for thetwo monomers is at least about 0.1, preferably at least about 0.2. Thedifference between the Log P value for the two monomers is preferablyless than about 2. The first and second monomers may be any monomerssuitable for producing a hydrogel composition, and include, but are notlimited to the monomers disclosed herein. The pendant anionic groups maybe sulphonic acid groups or salts thereof.

The Log P value herein refers to the octanol:water partitioncoefficient, which is a measurement known to those skilled in the art.It represents the distribution of a substance (in this context, amonomer) between two immiscible solvents at equilibrium. Log P is thelogarithm of the ratio of the mass concentration of the monomer inoctanol divided by the mass concentration of the monomer in water atequilibrium (measured at 1 atm, 25° C. and pH 7).

Log P may be defined as follows:

log P _(oct/wat)=log₁₀([monomer]_(octanol)/[monomer]_(water)),

wherein [monomer]_(octanol) is the mass concentration of the monomer inoctanol at equilibrium and [monomer]_(water) is the mass concentrationof the monomer in water at equilibrium.

Log P is preferably measured using the shake flask method known to thoseskilled in the art. Further description of this method may be found ingeneral textbooks and in the literature, such as in the review articleby Leo et al in Chem Rev 71 (6): 525-616 (1971).

Preferably the pendant anionic groups are predominantly sulphonyl andare even more preferably combinations of structurally differentsulphonyl groups. The structurally different pendant anionic groups mayalso be described by their relative hydrophilicity as exemplified by thecalculated octanol:water partition coefficient (Log P).

Estimates for Log P values for chemicals can be found by using onlinecalculation programs, including, but not limited to,www.molinspiration.com. Other methods may be used, such as the onedescribed in Perspectives in Drug Discovery and Design, 19: 47-66, 2000.The more negative the value of Log P the greater the partitioning intowater and hence the greater the hydrophilicity. For calculationsperformed on the monomers (calculated as the non ionised acid) on whichthe sulphonyl resides, the value of Log P for both monomers preferablyis less than 0, for the more hydrophilic monomer the value is preferablyless than about −1, more preferably less than about −1.5 even morepreferably less than about −1.9. For the first, less hydrophilic monomerthe value of Log P is greater than the second more hydrophilic monomerby preferably at least about 0.1, more preferably by about 0.2, butpreferably less than a difference of about 2.0.

The first monomer may have a Log P value greater (more positive than)than the second monomer. Preferably, the weight ratio (w/w) of the firstmonomer/second monomer in the hydrogel composition is equal to or morethan about 1, 1 more preferably about 1.5 or more, still more preferablyabout 2 or more, most preferably about 3 or more. The weight ratio (w/w)of the first monomer/second monomer in the hydrogel composition may befrom 1 to 3 or may be from 1 to 2. The molar ratio of the firstmonomer/second monomer in the hydrogel composition may be equal to ormore than about 1, 1 more preferably about 1.5 or more, still morepreferably about 2 or more, most preferably about 3 or more. The molarratio of the first monomer/second monomer in the hydrogel compositionmay be from 1 to 3 or may be from 1 to 2.

Thus if the sulphonyl monomers are identified as the first and secondsulphonyl monomers such that the first is the relatively lesshydrophilic according to the Log P values and the second is therelatively more hydrophilic according to the Log P values, then it ispreferred according to the present invention that the molar ratio of thefirst to the second sulphonyl monomers is between about 0:100 and about100:1, preferably between about 1:100 and about 100:1, more preferablybetween about 1:90 and about 90:1, more preferably between about 1:80 toabout 80:1, more preferably between about 1:50 and about 50:1, morepreferably between about 1:25 and about 25:1, more preferably betweenabout 1:10 and about 10:1, more preferably between about 1:5 and about5:1, more preferably between about 1:3 and about 3:1 and even morepreferably between about 1:3 and about 2:1.

Accordingly to a second aspect, the present invention provides ahydrogel composition, preferably for the treatment of wounds, comprisinga hydrophilic copolymer formed from a first monomer and a secondmonomer, wherein the first monomer comprises an olefinically unsaturatedsulphonic acid monomer or salt thereof, preferably an acrylic acid estersulphonic acid monomer or salt thereof, and the second monomer comprisesan olefinically unsaturated sulphonic acid monomer or salt thereof,different from the first monomer and preferably an acrylamide sulphonicacid monomer or salt thereof, the weight ratio (w/w) of the firstmonomer/second monomer in the hydrogel is equal to or more than 1 and,either (i) the sulphonic group in both first and second monomers is inacidic form or (ii) the sulphonic group in both first and secondmonomers is in salt form and the counterion for both monomers is thesame.

Preferably, the sulphonic group in both first and second monomers is insalt form and the counterion for both monomers is the same. Preferably,both first and second monomers are salts of olefinically unsaturatedsulphonic acid monomers. Preferably, the counterion for both salts isthe same, preferably sodium. Preferably, both first and second monomershave a Log P value of less than 0, and the difference between Log P forthe two monomers is at least about 0.1, preferably at least about 0.2.The difference between Log P between the two monomers is preferably lessthan about 1.

Reference to the “hydrogel composition of the present invention” hereinshall be synonymous with “the hydrogel composition of the first aspectof the invention and/or the hydrogel composition of the second aspect ofthe invention”.

The first monomer preferably comprises a compound of formula (I)

wherein R5 represents hydrogen or optionally substituted alkyl,preferably methyl or ethyl, R6 represents hydrogen or a cation and R7represents an optionally substituted alkylene moiety, preferably of 1 to4 carbon atoms. Preferably R7 represents optionally substitutedn-propyl. Unless otherwise indicated, the term “alkyl”, as used hereinincludes saturated monovalent hydrocarbon radicals having straight orbranched moieties, preferably containing 1 to 4 carbons. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, and t-butyl. Unless otherwise indicated, the term “alkylene”,as used herein, includes a divalent radical derived from straight-chainor branched alkane. Examples of alkylene radicals are methylene,ethylene (1,2-ethylene or 1,1-ethylene), propylene, trimethylene(1,3-propylene), tetramethylene (1,4-butylene), pentamethylene andhexamethylene.

R1, R2, R3, R4, R5 and R7 are optionally substituted by a group whichpreferably has a tendency to increase the water solubility of thecompound. Suitable groups will be well known to a person of skill in theart. A preferred optional substituent is a hydroxyl, amino or ammoniumgroup or a halogen (e.g. chlorine, bromine, or iodine) atom. A suitablecation is an alkali metal cation, especially sodium or potassium.

The second monomer preferably comprises a compound of formula (II)

wherein R1 is an optionally substituted hydrocarbon moiety, R2 ishydrogen or optionally substituted methyl and ethyl, and M representshydrogen or a cation.

R1 is preferably an optionally substituted alkylene, cycloalkylene or anaromatic moiety. Preferably R1 represents a saturated moiety or anaromatic moiety. R1 preferably contains from 3 to 12 carbon atoms, morepreferably from 3 to 6 carbon atoms. A preferred moiety which R1represents is

wherein R3 represents hydrogen or an optionally substituted straight orbranched chain alkyl group possessing from 1 to 6 carbon atoms and R4represents an optionally substituted straight or branched chain alkylgroup possessing from 1 to 6 carbon atoms.

Most preferably, the first monomer comprises an acrylic acid(3-sulphopropyl)ester or a salt thereof, e.g. an alkali metal salt suchas a sodium or potassium salt, of an analogue thereof. A particularlypreferred example is acrylic acid (3-sulphopropyl)ester sodium salt,which may be termed NaSPA or SPANa (available in the form of a solidfrom Raschig).

Most preferably, the second monomer is2-acrylamido-2-methylpropanesulphonic acid or a salt thereof, e.g. analkali metal salt such as a sodium or potassium salt. A particularlypreferred example is the sodium salt of2-acrylamido-2-methylpropanesulphonic acid (available commercially atpresent from Lubrizol as a 58% aqueous solution).

Most preferably, the hydrogel composition comprises a copolymer ofacrylic acid (3-sulphopropyl)ester sodium salt (NaSPA) and the sodiumsalt of 2-acrylamido-2-methylpropanesulphonic acid (NaAMPS), in whichthe weight ratio of NaSPA/NaAMPS in the polymer is 1 or more, preferably1.5 or more, more preferably 2 or more, still more preferably 3 or more.

Particular preferred examples of these respective monomers are thesodium salt of 2-acrylamido-2-methylpropanesulphonic acid, commonlyknown as NaAMPS, and acrylic acid (3-sulphopropyl)ester potassium salt,commonly known as SPA. NaAMPS is available commercially at present fromLubrizol as either a 50% aqueous solution (reference code LZ2405) or a58% aqueous solution (reference code LZ2405A). SPA is availablecommercially in the form of a solid from Raschig

The present invention further provides a method of treating a wound in ahuman or non-human mammal, particularly a human, comprising contactingthe wound for an effective period of time with a hydrogel composition ofthe present invention.

The present invention further provides the use of a hydrogel compositionof the present invention in the preparation of a topical medicament forthe treatment of a wound, for example a chronic skin lesion, in a humanor non-human mammal, particularly a human.

The hydrogel composition of the present invention may be for thetreatment of a wound, for example a chronic skin lesion, in a human ornon-human mammal, particularly a human.

The wound may be a skin wound. The wound may be a chronic ulcerous skinlesion. The chronic ulcerous skin lesion may be selected from venous legulcers, venous foot ulcers, arterial leg ulcers, arterial foot ulcers,decubitus ulcers (e.g. pressure sores, bedsores), post-surgical ulcerouslesions and chronic burn lesions.

The method of the present invention may comprise the contacting of thewound with the hydrogel composition of the present invention for aneffective period of time to promote healing with simultaneous reductionin one or more of pain, exudation, malodour, excoriation, spreading ofthe wound, tissue necrosis, irritation and hyperkeratosis.

The present invention further provides a method of treating skin-derivedor tissue-derived pain in a human or non-human mammal, particularly ahuman, by applying to the painful area as a topical dressing a hydrogelcomposition of the present invention.

The present invention further provides a method of inhibitinginflammation and/or the complement cascade and/or the kinin cascade in ahuman or non-human animal patient, comprising contacting an affectedlocation of the patient's body for an effective period of time with ahydrogel composition of the present invention.

The method may be used to treat an inflammation of an inflamed part of ahuman or non-human animal in which a wound is not present, including,but not limited to, inflamed, unbroken skin. The method may be used totreat dermatitis and/or psoriasis.

Broadly speaking, the hydrogels for use in the present invention havemultiple pendant sulphonyl groups, preferably multiple pendantstructurally different sulphonyl groups and optionally also multiplependant carboxylic groups and/or phosphonate groups, on each polymermolecule of the hydrogel.

By “pendant sulphonyl groups” we mean sulphonyl (—SO2-) containinggroups, most particularly sulpho (—SO2-OH) groups in acid or salt formor organic groups which include sulpho (—SO2-OH) groups in acid or saltform, which extend from the carbon atom containing chain (“carbonchain”) of the polymer molecule and are covalently linked (pendant) tothe carbon chain. Where the sulphonyl containing group is an organicgroup which includes the sulphonyl moiety, e.g. in a sulpho (—SO2-OH)group in acid or salt form, the sulphonyl moiety is preferably locatedat or near the terminal free end of the organic group, i.e. the enddistant from the carbon chain of the polymer molecule.

Some or all of the sulpho groups (—SO2-OH) groups in acid or salt formmay, if desired, be O-linked to the carbon chain of the polymermolecule, for example as organic sulphate groups. Some or all of thesulpho groups (—SO2-OH) groups in acid or salt form may, if desired, beC-linked to the carbon chain of the polymer molecule, for example asorganic sulphonate groups.

Where sulpho groups or some of them are present in salt form, the saltform may suitably be an alkali or alkaline earth or other multivalent(e.g. transition) metal or ammonium or organo-ammonium salt of the acidform (—SO2-OH). For example, the salt form may be the sodium, potassium,lithium, caesium, calcium, magnesium, zinc or ammonium salt orcombinations thereof. Preferably the salt form will comprise sodiumions, which may be in combination with one or more other salt forms suchas, for example, potassium or ammonium. A combination of sodium andpotassium counterions may be used. Most preferably, the counterions forfirst and second monomers are the same, most preferably sodium.

The organic sulphonyl containing groups or some of them may contain acarboxylate or carboxamido linkage unit. The polarity of these species,in conjunction with the sulphonyl groups, seems to play a part inachieving the desirable effects underlying the present invention. It ispreferred that the carboxylate or carboxamido linkage unit, whenpresent, is closer to the carbon chain of the polymer than the sulphonylmoiety.

By “pendant carboxylic groups” we mean carboxylate (—CO2-) containinggroups, most particularly carboxylic acid (—CO2H) groups in acid or saltform or organic groups which include carboxylic acid (—CO2H) groups inacid or salt form, which extend from the carbon atom containing chain(“carbon chain”) of the polymer molecule and are covalently linked(pendant) to the carbon chain. Where the carboxylate containing group isan organic group which includes the carboxylate moiety, the carboxylatemoiety is preferably located at or near the terminal free end of theorganic group, i.e. the end distant from the carbon chain of the polymermolecule.

Where carboxylic acid groups or some of them are present in salt form,the salt form may suitably be an alkali or alkaline earth or othermultivalent (e.g. transition) metal or ammonium or organo-ammonium saltof the acid form (—CO2H). For example, the salt form may be the sodium,potassium, or ammonium salt or combinations thereof. Preferably the saltform will comprise sodium ions, in combination with one or more othersalt forms such as, for example, potassium, or ammonium. A combinationof sodium and potassium counterions can be particularly suitable. Wherea combination of counterions is present in the hydrogel, any multivalentcounterion (e.g. one or more of magnesium, zinc, calcium) is suitablypresent in a total molar proportion of up to about 5 mol % relative tothe univalent (e.g. sodium) ions.

We have found that the hydrogels can be particularly effective when atleast some of the sulphonyl and, if present, carboxylic, groups arepresent in salt form and the nature and/or relative number of associatedcountercations are selected as described in more detail below.

The finding, for the first time in these hydrogels, of an intrinsiccontrollable interaction with proteins considerably enhances thepotential for the stimulation of wound healing and consequently makeseffective treatment available to a wider class of patients having arange of wound conditions, including chronic ulcerous skin lesions andin particular chronic leg and foot ulcers that are refractory to priorart treatments. Patients who have adverse reactions to specificanti-inflammatory chemicals, or for whom the administration of specificanti-inflammatory agents might risk allergic reactions, side effects orother disadvantages, will now benefit from the present invention. Thepresent invention assists in bringing the potential advantages of anovel anti-inflammatory treatment to the general public with reducedrisk of adverse effects. In addition, since the hydrogels used in thepresent invention also have other beneficial effects as noted above, thedressings are potentially of great benefit to patients who havereactions to certain classes of antibiotics, painkillers or otherbioactive agents conventionally used in, or in conjunction with, wounddressings, or who are addicted to or dependent on opiate or otherpowerful painkillers conventionally used in conjunction with wound care.Those people will be treatable using the present invention—in which theuse of other bioactive agents such as specific anti-inflammatory agents,antibiotics or painkillers can be avoided—whereas previous treatmentprotocols were restricted by the need to avoid the problematic chemicalagents such as anti-inflammatory agents, antibiotics, painkillers orother bioactive agents. Therefore, the novel findings constitute andmake available a novel therapeutic application.

The composition of the present invention preferably absorbs one or moreproteins, preferably fibrinogen. The composition of the presentinvention may initiate and/or promote clotting in a wound.

At least some of the pendant groups are preferably present in salt form,so that charge-balancing countercations other than H+ are present in thehydrogel associated with the pendant groups. The countercations may beselected from sodium, potassium, ammonium or organo-ammonium cations(primary ammonium, secondary ammonium, tertiary ammonium and quaternaryammonium cations). Two or more different countercations may be presentin the hydrogel, and may be selected from sodium, potassium, ammonium ororgano-ammonium cations (primary ammonium, secondary ammonium, tertiaryammonium and quaternary ammonium cations). Preferably, the countercationfor the first and second monomers is the same.

Two or more different countercations associated with pendant anionicgroups of the hydrogel, may be provided in a controlled relative molarproportion according to the extent of hydration of the countercations(i.e. according to the position of the countercations in the Hofmeisterseries of cations).

The polymers (including copolymers), both crosslinked andnon-crosslinked, of the invention preferably comprise pendant anionicgroups that are kosmotropic (water order makers) in nature. The cationiccounterion is preferably chaotropic (disorder maker) or, at most, weaklykosmotropic. The polymers of the invention may contain a mixture ofpendant anionic groups possessing different degrees of water ordermaking e.g. varying in kosmotropic strength, for example comprisingphosphate, phosphonate, sulphonyl, sulphate, sulphonate and carboxylateand combinations thereof. The extent of kosmotropic and chaotropicbehaviour has been quantified by thermodynamic parameters such as theJones Dole B viscosity coefficients. Preferred values of the Jones DoleB coefficient for the anion kosmotropic behaviour are greater than 0.1and preferably greater than 0.2. Preferred values of the Jones Dole Bcoefficient for the cation chaotropic behaviour are greater than −0.1.

The polymers of the invention may thus contain a mixture of chaotropicand kosmotropic ions. The molar ratio of chaotropic to kosmotropiccation is preferably less than about 500:1, for example less than about250:1, preferably less than about 200:1, for example less than about100:1, for example less than about 80:1, for example less than about50:1, and preferably more than about 2:1. For example, the ratio may bebetween about 2:1 and about 500:1, for example between about 5:1 andabout 200:1, for example between about 5:1 and about 100:1, for examplebetween about 7:1 and about 100:1, for example between about 10:1 andabout 100:1.

The polymers of the invention may also comprise combinations of pendantanionic group differing in the extent of the kosmotropic behaviour. Themolar ratio of pendant anionic kosmotropic groups with relatively largerJones Dole B viscosity coefficients (higher kosmotropic behaviour) topendant anionic kosmotropic groups with relatively smaller Jones Dole Bviscosity coefficients (lower kosmotropic behaviour) is preferablybetween about 1000:1 and about 1:1000, more preferably between about200:1 and about 1:200, and even more preferably between about 100:1 andabout 1:100.

Thus, if the countercations are identified as the first and secondcountercations such that the first is the relatively more stronglyhydrated according to the Hofmeister series of cations and the second isthe relatively more weakly hydrated according to the Hofmeister seriesof cations, then it is preferred according to the present invention thatwhen two or more countercations are present the molar ratio of the firstto the second countercations in the hydrophilic polymer is less thanabout 500:1, preferably less than about 200:1, for example less thanabout 100:1, for example less than about 80:1, for example less thanabout 50:1, and preferably more than about 2:1. For example, the ratiomay be between about 2:1 and about 500:1, for example between about 5:1and about 200:1, for example between about 5:1 and about 100:1, forexample between about 7:1 and about 100:1, for example between about10:1 and about 100:1.

The first cation may, for example, be sodium and the second may, forexample, be selected from potassium, primary ammonium, secondaryammonium, tertiary ammonium and quaternary ammonium, or the first may bepotassium and the second may be selected from primary ammonium,secondary ammonium, tertiary ammonium and quaternary ammonium. The firstcation is preferably sodium.

In one particular embodiment, the hydrophilic polymer is a copolymercomprising polymerised monomers carrying groups which provide thependant anionic (e.g. sulphonyl) groups of the polymer. One or moreadditional monomers may optionally be present in the polymer if desired,provided that the ionic balance of the polymer mentioned above ismaintained. At least some of the said pendant groups of the polymer arein salt form, preferably with a first countercation and a secondcountercation, different from the first. The said countercations areselected from relatively weakly hydrated cations according to theHofmeister series of cations, for example sodium, potassium, primaryammonium, secondary ammonium, tertiary ammonium and quaternary ammoniumcations. The countercations are preferably chosen such that the first isthe relatively more strongly hydrated according to the Hofmeister seriesof cations and the second is the relatively more weakly hydratedaccording to the Hofmeister series of cations. For example, the firstcation may be sodium and the second may be selected from potassium,primary ammonium, secondary ammonium, tertiary ammonium and quaternaryammonium, or the first may be potassium and the second may be selectedfrom primary ammonium, secondary ammonium, tertiary ammonium andquaternary ammonium

The molar ratio of the said first to the second countercations in thehydrophilic polymer is preferably less than about 500:1, preferably lessthan about 200:1, for example less than about 100:1, for example lessthan about 80:1, for example less than about 50:1, and preferably morethan about 2:1. For example, the ratio may be between about 2:1 andabout 500:1, for example between about 5:1 and about 200:1, for examplebetween about 5:1 and about 100:1, for example between about 7:1 andabout 100:1, for example between about 10:1 and about 100:1.

The polymer may suitably be formed by the polymerisation of monomers inwhich the groups which provide the pendant groups of the polymer are insalt form, such that the molar ratio of the monomer(s) in which the saltcation is the said first countercation in the hydrophilic polymer, tothe monomer(s) in which the salt cation is the said second countercationin the hydrophilic polymer, is, correspondingly, preferably less thanabout 250:1, preferably less than about 200:1, for example less thanabout 100:1, for example less than about 80:1, for example less thanabout 50:1, and preferably more than about 2:1. For example, the ratiomay be between about 2:1 and about 250:1, for example between about 5:1and about 200:1, for example between about 5:1 and about 100:1, forexample between about 7:1 and about 100:1, for example between about10:1 and about 100:1. These ratios relate to univalent molarequivalents; in the case of multivalent cations associated with the(univalent) anionic groups of the monomer(s), the molar amounts of themonomer(s) will be correspondingly adjusted.

By the relevant choice of the type of sulphonate monomer and the choiceof the countercation the interaction with proteins can be controlled asshown in the examples with the interaction with fibrinogen.

The hydrogel composition preferably comprises a polymer matrix holding aliquid (normally aqueous) phase retained within the hydrogel. Thepolymer matrix may for example be cross-linked or entangled, preferablycross-linked. The degree of cross-linking may be varied as desired. Thepolymeric matrix preferably consists of a cross-linked hydrophilicpolymer. The liquid phase may, if desired, incorporate one or more otherbioactive agents (e.g. particularly agents soluble or miscible in theliquid held within the polymer matrix of the hydrogel) to assist thehealing process of the chronic skin lesion, or may be free orsubstantially free of such bioactive agents. It is a preferred featureof the present invention, however, that the hydrogel composition per secan be effective for the healing of wounds, the inhibition ofinflammation and/or the complement cascade, without the need for otherbioactive agents. Therefore, in one embodiment of the present inventionthe hydrogel composition is substantially or entirely free of addedbioactive agents having specific therapeutic or other physiologicalactivity.

The hydrogel composition is preferably used in sheet form. The hydrogelcomposition is preferably prepared in sheet form by polymerisation of alaid down layer of a liquid pre-gel mixture of polymerisable components,which are then cured to provide the polymerised mass. Preferably all orsubstantially all of the desired components of the hydrogel composition,including any water, are present in the pre-gel, and that no orsubstantially no drying or other adjustments are required afterpolymerisation (apart from minor conventional conditioning).

The contacting of the wound with the hydrogel composition comprising ahydrophilic polymer carrying multiple pendant sulphonyl groups,optionally with multiple pendant carboxylic groups, on each polymermolecule preferably takes place for a period of time or for a sequenceof time periods to promote healing and/or the inhibition of inflammationand/or the complement cascade and/or the kinin cascade, preferably withsimultaneous reduction in one or more of pain, exudation, malodour,excoriation, spreading of the wound, tissue necrosis, irritation andhyperkeratosis.

The effective amount of pendant sulphonyl groups, optionally withmultiple pendant carboxylic groups, and the use of countercations forthe salt forms thereof, including selection of the nature and/or molarratio of any said two or more countercations present, for treating thewound, will vary from subject to subject.

The hydrophilic polymer used in the present invention may, if desired,comprise further multiple pendant anionic groups, in addition to thesulphonyl groups and optional carboxylic groups present. Where suchadditional anionic groups are present, they will typically be inrelatively small numbers in comparison with the sulphonyl and optionalcarboxylic groups. Any such additional anionic groups may be present inacid or salt form, provided that the ionic balance of the polymermentioned herein is maintained. Examples of such additional pendantanionic groups that may be present are relatively strongly hydratedanions according to the Hofmeister series of anions, for examplephosphate or phosphonyl groups.

A wound to be treated using any of the aspects of the present inventionmay be of any type, acute or chronic. The wound may for example be achronic ulcerous skin lesion, for example a malignant or pre-malignantchronic ulcerous skin lesion or a benign chronic ulcerous skin lesion.

The chronic ulcerous skin lesion may be a high exudation lesion, amedium exudation lesion or a low exudation lesion.

The hydrogel composition has the capacity to absorb many times (e.g. atleast about 2.5 times, for example at least about 5 times, for exampleat least about 10 times, for example between about 10 and about 50times) its own weight of exudate or other fluid in 24 hours. Therefore,the exudate management capacity of the composition can be selectedaccording to the intended target patients and lesions for treatment. Thehydrogel preferably has a water activity greater than about 0.4, forexample greater than about 0.5, for example greater than about 0.6, forexample greater than about 0.7, preferably greater than about 0.8,preferably greater than about 0.9, preferably greater than about 0.95,preferably greater than about 0.97 but less than about 0.99 in theabsence of maceration. In the presence of maceration the hydrogelpreferably has a water activity less than about 0.95, more preferablyless than about 0.9. As mentioned below, in some instances the wateractivity of the hydrogel may be substantially lower than about 0.4. Asdescribed in more detail below, one particularly suitable hydrogel foruse in the present invention may have a water activity in the range ofabout 0.6 to about 0.89.

As discussed in more detail below, the beneficial effects of thehydrogel according to the present invention are believed to derive fromthe presence of at least two or more structurally different sulphonylmonomers, optionally with multiple pendant carboxylic groups, of thepolymer molecules and the choice of the relevant counter cations. It isbelieved that these act in situ at the zone of contact with the wound tointeract more specifically than hither to possible with proteins thatlead to inhibit inflammation and/or the complement cascade, optionallywith other effects such as selectively concentrating one or morenaturally exuded salts in the ulcerous region of the lesion (the “woundbed”) and/or selectively absorbing one or more naturally exuded salts inthe wound bed (see WO2007/007115). The hydrogel thus acts without theneed for externally applied salt or other ionic aqueous solutions, andpreferably also in the absence of salt or other ionic aqueous solutionsin the liquid held within the polymer matrix of the hydrogel, so thatthe blocking mechanism preventing completion of the normal wound healingprocess is overridden, bypassed, shut off or otherwise disabled, andcontinuation of the normal wound healing process to substantialcompletion is enabled or initiated.

The selectivity of the anti-inflammatory effect is preferably achievedthrough the control of the counterion(s), if any, present on thesulphonyl groups or present on the multiple sulphonyl and carboxylicgroups and the nature of the sulphonyl group. Generally speaking, it isbelieved that selection of, say, sodium counterions on —SO3- groups(i.e. a sulpho group in salt form) will favour concentration of sodiumsalts (e.g. sodium chloride) in the wound bed, whereas selection of,say, potassium counterions on —SO3- groups will favour concentration ofpotassium salts (e.g. potassium chloride) in the wound bed whereasselection of, say, calcium counterions on —SO3- groups will favourconcentration of calcium salts (e.g. calcium chloride) in the wound bed.For example, we believe that it will be advantageous for the molar ratioof sodium ions to potassium ions associated in the hydrogel composition(or sodium ions to other more weakly hydrated cations according to theHofmeister series of cations) to be less than about 500:1, preferablyless than about 200:1, for example less than about 100:1, for exampleless than about 80:1, for example less than about 50:1, and preferablymore than about 2:1, for example, between about 2:1 and about 500:1, forexample between about 5:1 and about 200:1, for example between about 5:1and about 100:1, for example between about 7:1 and about 100:1, forexample between about 10:1 and about 100:1. Other counterions may alsobe used, as discussed above, in which case the molar ratios stated aboveapply instead to first and second cations in place of sodium andpotassium ions, the first being the relatively more strongly hydratedaccording to the Hofmeister series of cations and the second being therelatively more weakly hydrated according to the Hofmeister series ofcations.

From this, it is now possible to control the healing process in wounds,for example in chronic ulcerous skin lesions, for the first time,without the need for externally applied salts or other bioactive agentsapart from the dressing itself, and more particularly without the needfor salts or other bioactive agents in the dressing apart from thehydrogel polymer matrix (including the associated water and the ions ofthe hydrogel polymer) of the dressing itself.

The Hydrogel, Dressing and Treatment

The expression “hydrogel” and like expressions, used herein, are not tobe considered as limited to gels which contain water, but extendgenerally to all hydrophilic gels, including those containing organicnon-polymeric components in the absence of water. The gel forming agentmay, for example, be selected from natural hydrophilic polymers,synthetic hydrophilic polymers, gelling hydrophilic biopolymers and allcombinations thereof. The term “hydrogel” is used herein regardless ofthe state of hydration, and therefore includes, for example, hydrogelsthat are in a dehydrated or anhydrous state or in a state of partialhydration.

Hydrogels are described in greater detail in Hydrogels, Kirk-OthmerEncyclopedia of Chemical Technology, 4th Edition, vol. 7, pp. 783-807,John Wiley and Sons, New York, the contents of which are incorporatedherein by reference.

The expression “polymer” and like expressions, used herein, includeshomopolymers, copolymers and all mixtures and combinations thereof. Theexpression “polymer” and like expressions, used herein, includescross-linked and uncrosslinked polymers, as well as polymerscharacterised by entangled polymer chains. The expression “polymer” andlike expressions, used herein, includes bicontinuous and highermulticontinuous intermeshing polymer systems, in which two or morepolymers form identifiable intermeshing phases extending within thehydrogel mass.

Hydrogels are, generally speaking, hydrophilic polymers characterized bytheir hydrophilicity (i.e. capacity to absorb large amounts of fluidsuch as wound exudate) and insolubility in water: i.e. they are capableof swelling in water while generally preserving their shape.

The hydrophilicity is generally due to groups such as hydroxyl, carboxy,carboxamido, sulphonate and esters, among others. On contact with water,the hydrogel assumes a swollen hydrated state that results from abalance between the dispersing forces acting on hydrated chains andcohesive forces that do not prevent the penetration of water into thepolymer network. The cohesive forces are most often the result ofcrosslinking, but may result from electrostatic, hydrophobic ordipole-dipole interactions.

The hydrogels in the present invention include as a necessary componenta hydrophilic polymer carrying multiple pendant sulphonyl groups on eachpolymer molecule, preferably in salt form counterbalanced by one or morecations.

Generally, the degree of sulphonylation of such a polymer is on average(number average) at least about one pendant sulphonyl group per linear30 carbon atoms of the carbon atom backbone of the polymer, at leastabout one pendant sulphonyl group per linear 12 carbon atoms of thecarbon atom backbone of the polymer, for example at least about onependant sulphonyl group per linear six carbon atoms of the carbon atombackbone of the polymer. More preferably, the polymer will contain onaverage at least about two pendant sulphonyl groups per linear sixcarbon atoms of the carbon atom backbone of the polymer, for example upto about three pendant sulphonyl groups per linear six carbon atoms ofthe carbon atom backbone of the polymer. At the higher levels ofsulphonylation it is preferred that pendant carboxylate groups will besubstantially absent.

Most preferably, the polymer contains one pendant sulphonyl group perlinear two carbon atoms of the carbon atom backbone of the polymer. Sucha polymer is readily prepared by polymerising (meth)acrylic acidderivatives such as esters or amides using monomers containing onesulphonyl group per molecule. The sulphonyl groups may be present inacid, ester, salt or other suitable form, and may be covalently linkedto the carbon atom backbone of the polymer. A suitable sulphonyl moietyis the —SO3-species, either in acid form (—SO3H) or in salt form (—SO3M,where M is a univalent metal counterion, or —SO3MO3S— where M is adivalent metal counterion), or the organic sulphate species (forexample, —O—SO3H in acid form, or in corresponding salt form). Suitablelinking moieties include alkylene bridges, alkylene-ester bridges, —O—bridges and alkylene-amide bridges. The alkylene moieties may bestraight or branched, saturated and preferably contain from 1 to about 8carbon atoms.

Such hydrophilic polymers include, for example, polymers derived from(meth)acryloyloxyalkylsulphonates, polymers of sulpho-substitutedacrylamides such as acrylamidoalkanesulphonic acids, polymers of saltsof any of the foregoing (for example, alkali or alkaline earth metalsalts or ammonium or quaternary organ-ammonium salts), or anycombination thereof. Mixtures of such polymers with each other are alsoenvisaged.

Such polymers may, if desired, be used together with sulpho-freepolymers. Such other polymers, if present, may suitably be selected fromhomopolymers or copolymers of acrylic and methacrylic acid esters,including hydroxyalkyl(meth)acrylates, 2-(N,N-dimethylamino)ethylmethacrylate, polymers and copolymers of other substituted andunsubstituted acrylamides, polymers and copolymers ofN-vinylpyrrolidinone, and polyelectrolyte complexes.

The hydrophilic polymer carrying multiple pendant sulphonyl groups,optionally with multiple pendant carboxylic groups, on each polymermolecule should be present at least at the lesion-contacting surface ofthe hydrogel composition. If desired, the hydrophilic polymer carryingmultiple pendant sulphonyl groups, optionally with multiple pendantcarboxylic groups, on each polymer molecule may also be present in theinternal bulk of the composition, and/or a sulphonyl-free polymer orcombination of polymers may be present in the internal bulk of thecomposition.

Generally, the degree of carboxylation of such a polymer is on average(number average) at least about one pendant carboxylic group per linear100 carbon atoms of the carbon atom backbone of the polymer, for exampleup to about one pendant carboxylic group per linear six carbon atoms ofthe carbon atom backbone of the polymer.

The hydrogel used in the present invention suitably comprises asubstantially water-insoluble, slightly crosslinked, partiallyneutralized, gel-forming polymer material having the pendant sulphonylgroups, and optionally pendant carboxylic groups, in acid or salt format least at its lesion-contacting surface. Such polymer materials can beprepared from polymerizable, unsaturated, acid- and ester-containingmonomers. Any polymer to be present at the lesion-contacting surface ofthe composition will contain pendant sulphonyl groups, for example —SO3-in acid or salt form, and optionally carboxylic groups in acid or saltform, as described herein. Thus, such monomers include the olefinicallyunsaturated acids, esters and anhydrides which contain at least onecarbon to carbon olefinic double bond. More specifically, these monomerscan be selected from olefinically unsaturated carboxylic acids,carboxylic esters, carboxylic acid anhydrides; olefinically unsaturatedsulphonic acids; and mixtures thereof.

Olefinically unsaturated carboxylic acid, carboxylic acid ester andcarboxylic acid anhydride monomers include the acrylic acids typified byacrylic acid itself, methacrylic acid, ethacrylic acid, α-chloroacrylicacid, α-cyano-acrylic acid, β-methyl-acrylic acid (crotonic acid),α-phenyl acrylic acid, β-acryloxy-propionic acid, sorbic acid,α-chloro-sorbic acid, angelic acid, cinnamic acid, p-chloro-cinnamicacid, β-styryl-acrylic acid (1-carboxy-4-phenyl-1,3-butadiene), itaconicacid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid,maleic acid, fumaric acid, tricarboxy-ethylene and maleic acid anhydrideand salts (e.g. alkali metal salts such as sodium, potassium and lithiumsalts) thereof. For forming any polymer to be present at thelesion-contacting surface of the composition, the monomer or monomermixture will include a monomer containing pendant sulphonyl groups, e.g.—SO3- in salt form counter balanced by sodium and or potassium andammonium cations.

Olefinically unsaturated sulphonic acid monomers include aliphatic oraromatic vinyl sulphonic acids such as vinylsuiphonic acid,allylsulphonic acid, vinyltoluenesulphonic acid and styrene sulphonicacid; vinyl sulphobetaines such as SPDA (1-propanaminiumN,N-dimethyl-N-[2-[(1-oxo-2-propenyl)oxy]-3-sulfo hydroxide, inner salt(available from Raschig); acrylic and methacrylic sulphonic acid such assulphoethyl acrylate, sulphoethyl methacrylate, sulphopropyl acrylate,sulphopropyl methacrylate, 2-hydroxy-3-acryloxy propyl sulphonic acid,2-hydroxy-3-methacryloxy propyl sulphonic acid and2-acrylamido-2-methyl-propanesulphonic acid and salts (e.g. ammonium oralkali metal salts, such as sodium, potassium and lithium salts, oralkaline earth metal salts, such as calcium or magnesium) thereof.

The monomers may suitably be used in admixture with each other or withother monomers. In one particularly useful embodiment of the invention,a monomer which has a first countercation associated with it may be usedin admixture with one or more monomer which has/have one or moresecond/further countercation(s) associated with it/them, and preferablythe first countercation is the same as the second countercation. Themonomers in their anionic form (i.e. disregarding the counter-cation)may be the same or different. In this way, the proportions of differentcations (e.g. alkali metal ions such as sodium or potassium, or primary,secondary, tertiary or quaternary ammonium ions) can be finelycontrolled in the resultant polymer (homopolymer or copolymer), aspreviously discussed. The particular weight ratios of one monomer to theor each other monomer, and/or the respective countercations, can beselected within wide limits by those skilled in the art, depending onthe desired properties of the resultant hydrogel polymer, and examplesof suitable molar ratios have been given above in the

Further examples of suitable monomers for use in the present inventioninclude: a polyalkylene glycol acrylate or a substituted derivativethereof; a polyalkylene glycol methacrylate or a substituted derivativethereof; acrylic acid and salts thereof (e.g. alkali metal salts such assodium, potassium and lithium salts);2-acrylamido-2-methyl-propanesulphonic acid and salts thereof (e.g.ammonium or alkali metal salts, such as sodium, potassium and lithiumsalts, or alkaline earth metal salts, such as calcium or magnesium);acrylic acid (3-sulphopropyl)ester or a substituted derivative thereofor a salt thereof (e.g. an alkali metal salt such as sodium, potassiumor lithium salt); diacetone acrylamide(N-1,1-dimethyl-3-oxobutyl-acrylamide); a vinyl lactam (e.g. N-vinylpyrrolidone or a substituted derivative thereof); an optionallysubstituted N-alkylated acrylamide such as hydroxyethyl acrylamide; andan optionally substituted N,N-dialkylated acrylamide; and/or N-acryloylmorpholine or a substituted derivative thereof. For forming any polymerto be present at the lesion-contacting surface of the composition, themonomer or monomer mixture will include a monomer containing pendantsulphonyl groups, e.g. —SO3- in acid or salt form, and optionallycarboxylic groups in acid or salt form.

The above monomers and monomer types may optionally include substituentgroups. Optional substituents of the monomers used to prepare thehydrogels used in the present invention may preferably to selected fromsubstituents which are known in the art or are reasonably expected toprovide polymerisable monomers which form hydrogel polymers having theproperties necessary for the present invention. Suitable substituentsinclude, for example, lower alkyl, hydroxy, halo and amino groups.

In one particular form of the present invention, the hydrogel materialmay be free of uncrosslinked polymerised styrene sulphonates. In anotherparticular form of the present invention, the hydrogel material may befree of any styrene sulphonate component, whether polymerised orunpolymerised and whether crosslinked or uncrosslinked.

The hydrogel used in the present invention preferably comprises aplasticised three-dimensional matrix of cross-linked polymer molecules,and preferably has sufficient structural integrity to be self-supportingeven at very high levels of internal water content, with sufficientflexibility to conform to the surface contours of mammalian, preferablyhuman, skin or other surface with which it is in contact.

The hydrogel generally comprises, in addition to the cross-linkedpolymeric network, an aqueous or non-aqueous plasticising mediumincluding an organic plasticiser. This plasticising medium is preferablypresent in the same precursor solution as the monomer(s). Theplasticising medium may comprise additional ingredients in solution ordispersion, as described in more detail below.

The hydrogel composition may suitably be present as a thin sheet,preferably supported by a sheet support member to provide mechanicalstrength. The sheet support member for the hydrogel may, for example, bea thin scrim or net structure, for example formed of a synthetic and/ornatural polymer such as polyethylene or polypropylene. The sheet supportmember for the hydrogel may overlie the hydrogel sheet on the major faceof the sheet directed away from the lesion in use, or may be embeddedwithin the hydrogel polymer. The sheet support member may, if desired,extend beyond the margins of the hydrogel composition, and may beprovided with a skin adhesive portion to secure the dressing to theskin. The skin adhesive portion may be hydrogel in nature (for example aplasticised tacky hydrogel, which may be the same as or different fromthe hydrogel provided on the support member for the treatment accordingto the present invention), or may be another type of skin adhesiveselected from the many skin adhesives known in the wound dressings art.The support member may be or may comprise a sheet member as defined inWO 2007/113452, the contents of which is incorporated herein byreference. In particular, the support member may comprise or be a“fibrous absorbent sheet member” as defined in WO 2007/113452 and/or maycomprise one or more other sheet members defined as “other absorbentsheet members” in WO 2007/113452. The dressing of the present inventionmay comprise an optional “net member” as defined in WO 2007/113452.

The hydrogel sheet may be part of a multi-layer composite, includingfurther layers such as further hydrogels and/or other polymers and/orother sheet support members. For example, a breathable (air and/ormoisture permeable) polymeric film (e.g. of polyurethane) may overliethe hydrogel sheet or composite on the major face of the sheet orcomposite directed away from the lesion in use.

The hydrogel composition and other sheet components as desired maypreferably be provided with a release layer (e.g. of non-stick paper orplastic, such as siliconised paper or plastic) to protect one or bothmajor face of the sheet prior to use.

The hydrogel composition and other sheet components as desired canconstitute a dressing for the chronic ulcerous skin lesion which can,after removal of any release layer as appropriate, be applied to thelesion directly so that the major face which presents at its surface thehydrogel carrying pendant sulphonyl groups is directed towards thelesion and contacts the lesion, preferably the wound bed and surroundingtissues.

If desired, conventional bandages, cloths or other protective fabrics ormaterials can subsequently be applied to encase the dressing and hold itin place on the lesion.

Particularly where the hydrogel is plasticised, there is very slightadhesion between the hydrogel dressing and the patient's skin or thelesion tissue. This has the beneficial effect that one nurse or otherhealthcare professional can apply the dressing and can then prepare anydesired bandages, cloths or the like for subsequent application. Thedressing of the present invention will remain in place because of themild adhesion, even if the patient moves before the further bandagesetc. are applied.

The precursor liquid can comprise a solution of the gel-forming polymerin a relatively volatile solvent, whereby the hydrogel is deposited as aresidue on evaporation of the solvent, or—more preferably—the precursorliquid will comprise a solution of the monomer(s), cross-linking agent,plasticiser, and optionally water and other ingredients as desired,whereby the hydrogel is formed by a curing reaction performed on theprecursor liquid after application to the substrate to which thehydrogel is to be applied.

Preparation of the Hydrogel and Dressing

In the following discussion, the second form of precursor solution andapplication protocol (in situ polymerisation of the hydrogel) will bediscussed. The solvent deposition method carried out on a pre-formedgel-forming polymer is well known and the details of that procedure donot need to be reproduced here.

The polymerisation reaction is preferably a free-radical polymerisationwith cross-linking, which may for example be induced by light, heat,radiation (e.g. ionising radiation), or redox catalysts, as is wellknown.

For example, the free radical polymerisation may be initiated in knownmanner by light (photoinitiation), particularly ultraviolet light (UVphotoinitiation); heat (thermal initiation); electron beam (e-beaminitiation); ionising radiation, particularly gamma radiation (gammainitiation); non-ionising radiation, particularly microwave radiation(microwave initiation); or any combination thereof. The precursorsolution may include appropriate substances (initiators), at appropriatelevels, e.g. up to about 5% by weight, more particularly between about0.002% and about 2% by weight, which serve to assist the polymerisationand its initiation, in generally known manner.

Preferred photoinitiators include any of the following either alone orin combination:

Type I-α-hydroxy-ketones and benzilidimethyl-ketals e.g. Irgacure 651(2,2-dimethoxy-2-phenylacetophenone). These are believed on irradiationto form benzoyl radicals that initiate polymerisation. Photoinitiatorsof this type that are preferred are those that do not carry substituentsin the para position of the aromatic ring.

Preferred photoinitiators are 1-hydroxycyclohexyl phenyl ketone, forexample as marketed under the trade name Irgacure 184 by Ciba SpecialityChemicals; Irgacure 651 (2,2-dimethoxy-2-phenylacetophenone); Darocur1173 (2-hydroxy-2-propyl phenyl ketone); and mixtures of Irgacure 184and Darocur 1173.

Photo-polymerisation is particularly suitable, and may be achieved usinglight, optionally together with other initiators, such as heat and/orionising radiation. Photoinitiation will usually be applied bysubjecting the pre-gel reaction mixture containing an appropriatephotoinitiation agent to ultraviolet (UV) light. The incident UVintensity, at a wavelength in the range from 240 to 420 nm, is typicallygreater than about 10 mW/cm2. The processing will generally be carriedout in a controlled manner involving a precise predetermined sequence ofmixing and thermal treatment or history.

The UV irradiation time scale should ideally be less than 60 seconds,and preferably less than 10 seconds to form a gel with better than 95%conversion of the monomers. Those skilled in the art will appreciatethat the extent of irradiation will be dependent on a number of factors,including the UV intensity, the type of UV source used, thephotoinitiator quantum yield, the amount of monomer(s) present, thenature of the monomer(s) present and the presence of polymerisationinhibitor.

The precursor solution (pre-gel) containing the monomer(s) andpreferably cross-linking agent, water, plasticiser, photoinitiator andoptionally other components as described below, is initially laid downon a substrate. Where the hydrogel composition is to be prepared insheet for, the substrate will be a sheet. It may suitably comprise arelease layer and any desired sheet support member that may beinterposed between the release layer and the hydrogel composition, orembedded within the hydrogel composition, in the finished dressing. Inthis way, the precursor solution can be polymerised is situ on therelease layer, preferably with all or substantially all other componentsof the final dressing in place.

In one preferred embodiment, (on the one hand) the precursor solution incontact with the substrate to which it is to be applied and (on theother hand) the source of the polymerisation initiator (e.g. theradiation source) may move relative to one another for thepolymerisation step. In this way, a relatively large amount ofpolymerisable material can be polymerised in one procedure, more thancould be handled in a static system. This moving, or continuous,production system is preferred.

After completion of the polymerisation, the product is preferablysterilised in conventional manner. The sterile composite may be usedimmediately, e.g. to provide a skin-adhesive layer in an article, or atop release layer may be applied to the composite for storage andtransportation of the composite.

If desired, certain ingredients of the hydrogel may be added after thepolymerisation and optional cross-linking reaction. However, it isgenerally preferred that substantially all of the final ingredients ofthe hydrogel are present in the precursor solution, and that—apart fromminor conventional conditioning or, in some cases, subsequentmodifications caused by the sterilisation procedure—substantially nochemical modification of the hydrogel takes place after completion ofthe polymerisation reaction.

Monomers

The monomers are discussed in more detail above. Particularly preferredmonomers include: the sodium salt of 2-acrylamido-2-methylpropanesulphonic acid, commonly known as NaAMPS, which is availablecommercially at present from Lubrizol as either a 50% aqueous solution(reference code LZ2405) or a 58% aqueous solution (reference codeLZ2405A); the potassium salt of 2-acrylamido-2-methylpropane sulphonicacid (Potassium AMPS), which is available commercially at present fromLubrizol; the ammonium salt of 2-acrylamido-2-methylpropane sulphonicacid (Ammonium AMPS), which is available commercially at present fromLubrizol; acrylic acid (3-sulphopropyl)ester potassium salt, commonlyknown as SPA or SPAK (SPA or SPAK is available commercially in the formof a pure solid from Raschig); acrylic acid (3-sulphopropyl)ester sodiumsalt, commonly known as SPANa (SPANa is available commercially in theform of a pure solid from Raschig); and SPDA. Acrylic acid (BASF) may beused as supplied or in partial or complete salt form where the saltcounterion is an alkali metal (e.g. sodium or potassium), alkaline earthmetal (e.g. calcium) or ammonium. Mixtures of any two or more of theabove monomers may be used. When a mixture of the monomers is used, itmay, for example, be a mixture of NaAMPS and SPAK, a mixture of NaAMPSand SPANa, a mixture of NaAMPS and Potassium AMPS, a mixture of NaAMPSand Ammonium AMPS, or a mixture of NaAMPS and acrylic acid. The relativeamounts of the monomers in a mixture will be dictated by the desiredratio of counterions (e.g. potassium, sodium and ammonium) in thehydrogel, as well as the required properties of the copolymer, and maybe selected easily by those skilled in the art, if necessary withroutine testing of the copolymers prepared.

Cross-Linking Agents

Conventional cross-linking agents are suitably used to provide thenecessary mechanical stability and to control the adhesive properties ofthe hydrogel. The amount of cross-linking agent required will be readilyapparent to those skilled in the art such as from about 0.01% to about0.5%, particularly from about 0.05% to about 0.4%, most particularlyfrom about 0.08% to about 0.3%, by weight of the total polymerisationreaction mixture. Typical cross-linkers include tripropylene glycoldiacrylate, ethylene glycol dimethacrylate, triacrylate, polyethyleneglycol diacrylate (polyethylene glycol (PEG) molecular weight betweenabout 100 and about 4000, for example PEG400 or PEG600), and methylenebis acrylamide.

Organic Plasticisers

The one or more organic plasticiser, when present, may suitably compriseany of the following either alone or in combination: at least onepolyhydric alcohol (such as glycerol, polyethylene glycol, or sorbitol),at least one ester derived therefrom, at least one polymeric alcohol(such as polyethylene oxide) and/or at least one mono- or poly-alkylatedderivative of a polyhydric or polymeric alcohol (such as alkylatedpolyethylene glycol). Glycerol is the preferred plasticiser. Analternative preferred plasticiser is the ester derived from boric acidand glycerol. When present, the organic plasticiser may comprise up toabout 45% by weight of the hydrogel composition.

Surfactants

Any compatible surfactant may optionally be used as an additionalingredient of the hydrogel composition. Surfactants can lower thesurface tension of the mixture before polymerisation and thus aidprocessing. The surfactant or surfactants may be non-ionic, anionic,zwitterionic or cationic, alone or in any mixture or combination. Thesurfactant may itself be reactive, i.e. capable of participating in thehydrogel-forming reaction. The total amount of surfactant, if present,is suitably up to about 10% by weight of the hydrogel composition,preferably from about 0.05% to about 4% by weight.

The surfactant may, for example, comprise at least one propyleneoxide/ethylene oxide block copolymer, for example such as that suppliedby BASF Plc under the trade name Pluronic P65 or L64.

Other Additives

The hydrogel in the composite of the present invention may include oneor more additional ingredients, which may be added to thepre-polymerisation mixture or the polymerised product, at the choice ofthe skilled worker. Such additional ingredients are selected fromadditives known in the art, including, for example, water, organicplasticisers, surfactants, polymeric material (hydrophobic orhydrophilic in nature, including proteins, enzymes, naturally occurringpolymers and gums), synthetic polymers with and without pendantcarboxylic acids, electrolytes, osmolites, pH regulators, colorants,chloride sources, bioactive compounds and mixtures thereof. The polymerscan be natural polymers (e.g. xanthan gum), synthetic polymers (e.g.polyoxypropylene-polyoxyethylene block copolymer or poly-(methyl vinylether alt maleic anhydride)), or any combination thereof. By “bioactivecompounds” we mean any compound or mixture included within the hydrogelfor some effect it has on living systems, whether the living system bebacteria or other microorganisms or higher animals such as the patient.Bioactive compounds that may be mentioned include, for example,pharmaceutically active compounds, antimicrobial agents, antisepticagents, antibiotics and any combination thereof. Antimicrobial agentsmay, for example, include: sources of oxygen and/or iodine (e.g.hydrogen peroxide or a source thereof and/or an iodide salt such aspotassium iodide) (see, for example Bioxzyme™ technology, for example inThe Sunday Telegraph (UK) 26 Jan. 2003 or the discussion of the Oxyzyme™system at www.wounds-uk.com/posterabstracts2003.pdf); honey (e.g. activeManuka honey); antimicrobial metals, metal ions and salts, such as, forexample, silver-containing antimicrobial agents (e.g. colloidal silver,silver oxide, silver nitrate, silver thiosulphate, silver sulphadiazine,or any combination thereof), hyperchlorous acid; or any combinationthereof.

In the Bioxzyme system, a dressing comprises two hydrogels. One containsglucose based antibacterial compounds and the other contains enzymesthat convert the glucose into hydrogen peroxide. When these are exposedto air and contacted together at a wound site, the enzyme-containing gelbeing adjacent the skin and the glucose-containing gel overlying theenzyme-containing gel, a low level steady flow of hydrogen peroxide isproduced, which inhibits anaerobic bacteria. This antibacterial effectcan be enhanced by the inclusion of a very low level of iodide (lessthan about 0.04%) in the hydrogel. The hydrogen peroxide and the iodidereact to produce iodine, a potent antimicrobial agent.

Hydrogels incorporating antimicrobial agents may, for example, be activeagainst such organisms as Staphylococcus aureus and Pseudomonasaeruginosa.

Agents for stimulating the healing of wounds and/or for restricting orpreventing scarring may be incorporated into the hydrogel. Examples ofsuch agents include growth factors such as TGF (transforming growthfactor), PDGF (platelet derived growth factor), KGF (keratinocyte growthfactor, e.g. KGF-1 or KGF-2), VEGF (vascular endothelial growth factor),IGF (insulin growth factor, optionally in association with one or moreof IGF binding protein and vitronectin), e.g. from GroPep Ltd, Australiaor Procyte, USA (see, e.g. WO-A-96/02270, the contents of which areincorporated herein by reference); cell nutrients (see, e.g.,WO-A-93/04691, the contents of which are incorporated herein byreference); glucose (see, e.g., WO-A-93/10795, the contents of which areincorporated herein by reference); an anabolic hormone or hormonemixture such as insulin, triiodothyronine, thyroxine or any combinationthereof (see, e.g., WO-A-93/04691, the contents of which areincorporated herein by reference); or any combination thereof.

Additional polymer(s), typically rheology modifying polymer(s), may beincorporated into the polymerisation reaction mixture at levelstypically up to about 10% by weight of total polymerisation reactionmixture, e.g. from about 0.2% to about 10% by weight. Such polymer(s)may include polyacrylamide, poly-NaAMPS, polyethylene glycol (PEG),polyvinylpyrrolidone (PVP) or carboxymethyl cellulose.

Additional osmolite(s) may be included to modify the osmolarity of thehydrogel. Osmolites may be ionic (e.g. electrolytes, for example saltswhich are readily soluble in the aqueous phase of the hydrogel toincrease the ionic strength of selected cations or anions and hence theosmolarity of the hydrogel). By selecting the ions present in an ionicosmolite, and particularly by selecting the cation so as to correspondor not with cationic counterions in the monomer(s) of the hydrogel, theionic strength of certain anions (e.g. chloride) can be varied with finecontrol, without substantially changing the ionic strength of cationsalready present in very large amounts as counterions of the monomer(s).

Osmolites may be organic (non-ionic), for example organic moleculeswhich dissolve in or intimately mix with the aqueous phase of thehydrogel to increase the osmolarity of the hydrogel deriving fromnon-ionic species in the aqueous phase. Such organic osmolites include,for example, water-soluble sugars (e.g. glucose and othermonosaccharides), polyhydric alcohols (e.g. glycerol and otherpolyhydroxylated alkanols).

Additive ingredients may serve more than one purpose. For example,glycerol may serve as an organic plasticiser and an osmolite.

The hydrogel may comprise one or more complexing or chelating agents,which may include, but are not limited to, organic poly-carboxylicacids, and includes, but is not limited to, agents that can formcomplexes with or chelate to one or more metal ions. The complexingagent may be selected from di-, tri- and tetra-carboxylic acids.Preferably, the one or more complexing or chelating agents contain amoiety in which two carboxylic acid groups (CO₂H) or salts thereof areseparated by three or four covalent bonds (e.g. three bonds in malicacid: (HO₂C)—CH₂—CH, OH—(CO₂H); four bonds in EDTA:(HO₂C)—CH₂—NR—CH₂—(CO₂H), in which R is the remaining part of themolecule). The complexing or chelating agents may comprise one or moremolecules containing one or more primary, secondary or tertiarynitrogens within their structure. The complexing or chelating agents mayinclude, but are not limited to, EDTA, citric acid, maleic acid, malicacid, and their salts (which include, but are not limited to, sodium andpotassium salts). These agents have been found to be effective incontrolling any ion exchange that may be associated with the hydrogelcomposition. The chelating agents may be present in an amount of from0.01 to 10% by weight of the prepolymer mixture, preferably from 0.01 to2% by weight of the prepolymer mixture.

The hydrogel used in the present invention preferably consistsessentially of a cross-linked hydrophilic polymer of a hydrophilicmonomer and optionally one or more comonomer, together with water and/orone or more organic plasticiser, and optionally together with one ormore additives selected from surfactants, polymers, pH regulators,electrolytes, osmolites, chloride sources, bioactive compounds andmixtures thereof, with less than about 40%, for example less than about10%, by weight of other additives.

For further details of suitable hydrogel material for use in the presentinvention, and its preparation, please refer to the followingpublications: PCT Patent Applications Nos. WO-97/24149, WO-97/34947,WO-00/06214, WO-00/06215, WO-00/07638, WO-00/46319, WO-00/65143 andWO-01/96422, the disclosures of which are incorporated herein byreference.

The water activity, which is related to the osmolarity and the ionicstrength of the precursor solution (as measured, for example, by achilled mirror dewpoint meter, Aqualab T3) is preferably between 0.05and 0.99, more preferably between, 0.2 and 0.99, and even morepreferably between 0.3 and 0.98, for example between 0.6 and 0.89. Theionic strength of the precursor solution can therefore be used tooptimise the hydrogel properties.

EXAMPLES

The following non-limiting examples are provided as further illustrationof the present invention, but without limitation.

In the following Examples, and throughout this description, parts andpercentages are by weight unless otherwise stated.

Example 1

Pre-gel: 23 parts by weight of 58% aqueous solution of the sodium saltof acrylamidomethyl-propanesulphonic acid (NaAMPS, LZ2405 Lubrizol), 32parts acrylic acid (3-sulphopropyl)ester sodium salt, commonly known asSPA or SPANa (SPA or SPANa is available in the form of a solid fromRaschig), 37 parts water, 10 parts glycerol and 0.1 parts of a 1 to 10(by weight) mixture of Daracure 1173 photoinitiator (Ciba SpecialityChemicals) and IRR280 cross-linker (PEG400 diacrylate, UCB Chemicals).

Example 2

Pre-gel: 23 parts by weight of 58% aqueous solution of the sodium saltof acrylamidomethyl-propanesulphonic acid (NaAMPS, LZ2405 Lubrizol), 32parts acrylic acid (3-sulphopropyl)ester potassium salt, commonly knownas SPA or SPAK (SPA or SPAK is available commercially in the form of apure solid from Raschig), 37 parts water, 10 parts glycerol and 0.1parts of a 1 to 10 (by weight) mixture of Daracure 1173 photoinitiator(Ciba Speciality Chemicals) and IRR280 cross-linker (PEG400 diacrylate,UCB Chemicals).

Example 3

Pre-gel: 35 parts by weight of 58% aqueous solution of the sodium saltof acrylamidomethyl-propanesulphonic acid (NaAMPS, LZ2405 Lubrizol), 20parts acrylic acid (3-sulphopropyl)ester sodium salt, commonly known asSPA or SPANa (SPA or SPANa is available in the form of a solid fromRaschig), 37 parts water, 10 parts glycerol and 0.1 parts of a 1 to 10(by weight) mixture of Daracure 1173 photoinitiator (Ciba SpecialityChemicals) and IRR280 cross-linker (PEG400 diacrylate, UCB Chemicals).

Example 4

Pre-gel: 35 parts by weight of 58% aqueous solution of the sodium saltof acrylamidomethyl-propanesulphonic acid (NaAMPS, LZ2405 Lubrizol), 20parts acrylic acid (3-sulphopropyl)ester potassium salt, commonly knownas SPA or SPAK (SPA or SPAK is available commercially in the form of apure solid from Raschig), 37 parts water, 10 parts glycerol and 0.1parts of a 1 to 10 (by weight) mixture of Daracure 1173 photoinitiator(Ciba Speciality Chemicals) and IRR280 cross-linker (PEG400 diacrylate,UCB Chemicals).

Example 5

Pre-gel: 67 parts by weight of 58% aqueous solution of the sodium saltof acrylamidomethyl-propanesulphonic acid (NaAMPS, LZ2405 Lubrizol), 0.5parts acrylic acid (3-sulphopropyl)ester potassium salt, commonly knownas SPA or SPAK (SPA or SPAK is available commercially in the form of apure solid from Raschig), 20 parts water, 10 parts glycerol and 0.1parts of a 1 to 10 (by weight) mixture of Daracure 1173 photoinitiator(Ciba Speciality Chemicals) and IRR280 cross-linker (PEG400 diacrylate,UCB Chemicals).

Example 6

Pre-gel: 67 parts by weight of 58% aqueous solution of the sodium saltof acrylamidomethyl-propanesulphonic acid (NaAMPS, LZ2405 Lubrizol), 20parts water, 10 parts glycerol and 0.1 parts of a 1 to 10 (by weight)mixture of Daracure 1173 photoinitiator (Ciba Speciality Chemicals) andIRR280 cross-linker (PEG400 diacrylate, UCB Chemicals).

The change in specificity of the interaction of these gels with proteinsis exemplified below with fibrinogen. The Example gels are immersed in afibrinogen solution for 22 hours and the concentration of fibrinogen inthe supernatant is measured by gel permeation chromatography. A relativedecrease in fibrinogen concentration is indicative of an enhancedinteraction.

Materials and Methods

Gel Permeation Chromatography

Column: Zorbax GF250 9.4×250 mm 4μ (Agilent Technologies)

Guard: Zorbax DIOL 9.4×15 mm 7μ (Agilent Technologies)

HPLC Solvent Pump: Prostar 230 (Varian)

HPLC Autosampler: Prostar 410 (Varian)

HPLC Detector: Prostar 330 (Varian)

-   -   UV Deuterium Lamp (Varian)

Software Varian Star Chromatography Workstation (v 5)

All reagents were used as supplied: HPLC grade methanol and water(Fisher Scientific) and analytical reagent grade Na2HPO4(Riedel-de-Haen).

Molecular Weight Marker Kit: Kit for Molecular Weights 12,000-200,000,For Gel Permeation Chromatography (Sigma-Aldrich).

Fibrinogen Calcium Saline Solution Preparation

Fibrinogen (0.2-0.27 g, 71% purity, Fluka) was dissolved in calciumsaline solution (0.81-0.85 g NaCl and 0.027-0.029 g CaCl2 per 100 gwater). The mixture was stirred for half an hour at room temperature toensure maximum dissolution.

Fibrinogen Solution—Hydrogel Experiment

A piece of hydrogel (0.035-0.06 g) had all detachable liners removed andwas inserted into a microcentrifuge tube (1.5 ml, polypropylene) ofknown tare weight. The weight of the hydrogel was recorded. Fibrinogencalcium saline solution (25 times the weight of the hydrogel) wascharged to the tube using a microlitre pipette with pipette tips(200-1000 μl, Fisherbrand®, FB34611), and the weight of solution wasrecorded. The tube was sealed using the cliplock top. The tube wasinverted three times to ensure the hydrogel was not stuck to the vesselwalls; if the hydrogel did adhere to the tube then gentle tapping wasapplied to the outside to release it. All samples were prepared in thisway and the start time of each experiment was noted. A blank sample(with no gel) was also prepared in the same manner. The samples werestored in ambient conditions.

After the allotted time period had elapsed (22 hrs), the time of thereaction was recorded. The experiment was stopped by carefully removingthe hydrogel from the tube and transferring it to a clean taredmicrocentrifuge tube (1.5 ml, polypropylene). The weight of the gel wasrecorded. All experiments were exposed to the gel for the same period oftime.

The remaining supernatant was extracted from the microcentifuge tubewith a sterile disposable syringe (1.0 ml, polypropylene). A syringefilter (13 mm, 0.2 μm PTFE membrane, PP housing) was attached to thesyringe and the mixture was filtered, to remove any solids, into a shortthread vial (1.5 ml, amber, Varian). The vial was sealed with a screwcap (polypropylene, Varian).

GPC Calibration

Bovine Serum Albumin (0.01 g, BSA) was dissolved in buffered saline(0.1M NaCl 0.02M Na2HPO4 in 5% methanol/water) and made up to volume ina volumetric flask (25 ml). The protein solution was filtered through asyringe filter (13 mm, 0.2 μm PTFE membrane, PP housing) into a shortthread vial (1.5 ml, amber, Varian). The vial was sealed with a screwcap (polypropylene, Varian).

The BSA solution (25 μl) was injected into the HPLC with an autosampler.The HPLC conditions were as follows:

Column: Zorbax GF250 9.4×250 mm 4μ (Agilent Technologies)

Guard: Zorbax DIOL 9.4×15 mm 7μ (Agilent Technologies)

Mobile Phase: 0.2M Na2HPO4 in 5% methanol/water

Flow rate: 0.8 ml·min-1

Run time: 30 mins

Temp: 30° C.

Detector wavelength: 215 nm

Molecular weight markers from the Kit for Molecular Weights12,000-200,000 (Sigma-Aldrich) were prepared in the same manner as theBSA solution, using the following concentrations: Cytochrome C (0.0037 gin 25 ml); Carbonic Anhydrase (0.0057 g in 25 ml); Alcohol dehydrogenase(0.0058 g in 25 ml); β-amylase (0.0046 g in 25 ml).

GPC on Protein Samples

Fibrinogen solutions were prepared as described earlier and analysed bygel permeation chromatography using the conditions outlined earlier inthis document.

Chromatographic Analysis

Peak height and peak area determination was performed with Varian StarChromatography Workstation (v 5) software package.

Results

See Tables 1 to 6 below and FIGS. 1 to 3 for results and graphs basedthereon:

Table 1 shows molecular weight markers and retention time data in thegel permeation chromatography test, as described above.

Mw Markers Molecule Mw Log₁₀Mw Rt Ve/V0 Blue Dextran 2000000 6.30 9.341.00 Bovine Serum Albumin 66430 4.82 11.49 1.23 Cytochrome C 12400 4.0915.20 1.63 Carbonic Anhydrase 29000 4.46 13.50 1.45 AlcoholDehydrogenase 150000 5.18 11.07 1.19 β-amylase 200000 5.30 10.65 1.14

FIG. 1 shows the results of Table 1 in a graph of retention time (mins)versus Log 10 molecular weight.

Table 2 shows results for peak area versus concentration test. Linearity(Peak Area).

Validation: Linearity (Fibrinogen)

Peak Area [Fibrinogen]/ g/ml Mean Area STDEV Samples 0.000229 1.44E+073.01E+06 5 0.001016 7.21E+07 7.66E+06 6 0.001751 1.28E+08 5.14E+06 60.002052 1.56E+08 2.46E+06 5 0.003272 2.43E+08 2.15E+06 3

FIG. 2 shows the results of Table 2 in a graph of peak area (units)versus fibrinogen concentration (g/ml). Error bars are standarddeviation.

Table 3 shows linearity for peak area versus concentration forfibrinogen:

Linearity (Peak Area) R² = 0.999 y₀ = −3.25e⁶ m = 5.4e¹⁰

Table 4 shows results for peak height versus concentration test forfibrinogen:

Peak Height [Fibrinogen]/g/ml Mean Area STDEV Samples 0.000229 7.96E+042.01E+04 5 0.001016 4.63E+05 5.63E+04 6 0.001751 8.89E+05 4.95E+04 60.002052 1.12E+06 2.64E+04 5 0.003272 1.90E+06 3.66E+04 3

Table 5 shows results for peak height linearity for fibrinogen:

Linearity (Peak Height) R² = 0.995 y₀ = −1.15e⁵ m = 6.04e⁸

Table 6 shows the fibrinogen concentration in an aqueous calcium salinesolution after 24 hrs exposure to a hydrogel totally immersed in thefibrinogen solution:

[Fibrinogen] Average [Fib] Replicate Replicate GEL g/100 ml g/100 mlSTDEV Variance Example 2.66E−03 0.005 3.10E−03 9.61E−06 1 7.05E−03Example 7.87E−02 0.094 2.15E−02 4.61E−04 2 1.09E−01 Example 1.44E−020.026 1.66E−02 2.77E−04 3 3.79E−02 Example 1.18E−01 0.123 7.38E−035.44E−05 4 1.29E−01 Example 1.30E−01 0.130 2.50E−04 6.26E−08 5 1.31E−01Example 1.08E−01 0.118 1.40E−02 1.96E−04 6 1.28E−01

FIG. 3 shows the results from Table 6 in a chart of fibrinogenconcentration in supernatant fluid (g/100 ml) after 22 hrs exposure tosix different hydrogels of Examples 1 to 6.

The high degree of linearity in both the peak area vs concentration testand the peak height vs concentration test indicates that either peakarea or peak height, as measured on a calibrated HPLC apparatus, mayreliably be used to determine the concentration of fibrinogen insolution.

The data in Table 6 and FIG. 3 clearly show that enhanced interactionwith fibrinogen is obtained when a high concentration of NaSPA is usedrelative to the co-monomer, NaAMPS. It appears that hydrogels ofExamples 1 and 3 were surprisingly able to absorb more fibrinogen thanthe hydrogels of the other Examples. The corresponding KSPA, NaAMPScopolymers do not show the enhanced interaction. These data clearlydemonstrate the importance of both the anion and counter cation in thehydrogel polymers for controlling interactions with proteins.

The present invention provides an effective method of inhibition ofinflammation, useful for example (but not exclusively) in the treatmentof wounds, for example chronic skin lesions such as ulcerated skinlesions (e.g. chronic venous or arterial leg ulcers) to promote theirhealing.

In the context of the treatment of wounds, the method makes availableinhibition of inflammation and/or the complement cascade and/or thekinin cascade, and potentially simultaneous reduction of one or moreundesirable characteristics of a wound, for example a chronic skinlesion, selected from pain associated with the wound, pain associatedwith changing of the dressing, exudation, malodour, irritation andhyperkeratosis, as has already been described in our PCT patentapplication No. PCT/GB2006/002632 (WO2007/007115).

Undesirable effects of conventional dressings for wounds such as chronicskin lesions, for example maceration, incomplete absorption of exudate,excoriation, scarring of the final healed tissue, contact dermatitis,varicose eczema or skin stripping can also be reduced using the presentinvention in the context of wound treatment.

The hydrogel (dressing) used in the present invention is easy to applyand change, with resultant cost savings and efficiency enhancements.

The above broadly describes the present invention, without limitation.Variations and modifications as will be readily apparent to those ofordinary skill in this art are intended to be covered by thisapplication and all subsequent patents.

1. A hydrogel composition for the treatment of wounds, comprising ahydrophilic co-polymer carrying multiple pendant anionic groups, whereinthe polymer is derived from a first monomer and a second monomer,wherein both monomers have an octanol:water partition coefficient Log Pvalue of less than 0, wherein the first monomer has a Log P valuegreater (more positive) than the second monomer and the weight ratio(w/w) of the first monomer/second monomer in the hydrogel composition isequal to or more than about
 1. 2. A hydrogel composition according toclaim 1, wherein both the first and second monomers comprise a pedantanionic group in acid or salt form and, either (i) the anionic group inboth first and second monomers is in acidic form or (ii) the anionicgroup in both first and second monomers is in salt form and thecounterion for both monomers is the same.
 3. A hydrogel composition forthe treatment of wounds, comprising a hydrophilic copolymer formed froma first monomer and a second monomer, wherein the first monomercomprises an acrylic acid ester sulphonic acid monomer or salt thereof,and the second monomer comprises an acrylamide sulphonic acid monomer orsalt thereof, the weight ratio (w/w) of the first monomer/second monomerin the hydrogel is equal to or more than about 1 and, either (i) thesulphonic group in both first and second monomers is in acidic form or(ii) the sulphonic group in both first and second monomers is in saltform and the counterion for both monomers is the same.
 4. A hydrogelcomposition according to claims 1 or 3, wherein the first monomer is acompound of formula (I)

wherein R5 represents hydrogen or optionally substituted alkyl,preferably methyl or ethyl, R6 represents hydrogen or a cation and R7represents an optionally substituted alkylene moiety containing 1 to 4carbon atoms.
 5. A hydrogel composition according to claim 4, whereinthe second monomer comprises a compound of formula (II)

wherein R1 is an optionally substituted hydrocarbon moiety, R2 ishydrogen or optionally substituted alkyl, and M represents hydrogen or acation.
 6. A hydrogel composition according to claim 5, wherein theweight ratio (w/w) of the first monomer/second monomer is about 2 ormore.
 7. A hydrogel composition according to claim 6, wherein the weightratio (w/w) of the first monomer/second monomer is about 3 or more.
 8. Ahydrogel composition according to claim 3, wherein both first and secondmonomers have a Log P value of less than 0, and the difference betweenLog P for the two monomers is at least about 0.1 and is less than about2.
 9. A hydrogel composition according to claim 3 for the treatment of awound in a human or non-human mammal.
 10. A hydrogel compositionaccording to claim 9, wherein the wound is a chronic ulcerous skinlesion.
 11. A hydrogel composition according to claim 10, wherein thewound is selected from venous leg ulcers, venous foot ulcers, arterialleg ulcers, arterial foot ulcers, decubitus ulcers (e.g. pressure sores,bedsores), post-surgical ulcerous lesions and chronic burn lesions. 12.A method of treating a wound in a human or non-human mammal, comprisingcontacting the wound for an effective period of time with a hydrogelcomposition, wherein the hydrogel composition comprises (i) ahydrophilic co-polymer carrying multiple pendant anionic groups, whereinthe polymer is derived from a first monomer and a second monomer,wherein both monomers have an octanol:water partition coefficient Log Pvalue of less than 0, wherein the first monomer has a Log P valuegreater (more positive) than the second monomer and the weight ratio(w/w) of the first monomer/second monomer in the hydrogel composition isequal to or more than about 1; or (ii) a hydrophilic copolymer formedfrom a first monomer and a second monomer, wherein the first monomercomprises an acrylic acid ester sulphonic acid monomer or salt thereof,and the second monomer comprises an acrylamide sulphonic acid monomer orsalt thereof, the weight ratio (w/w) of the first monomer/second monomerin the hydrogel is equal to or more than about 1 and, either (i) thesulphonic group in both first and second monomers is in acidic form or(ii) the sulphonic group in both first and second monomers is in saltform and the counterion for both monomers is the same.
 13. A methodaccording to claim 12, wherein an effective period of time promoteshealing with a simultaneous reduction in one or more of: pain,exudation, malodour, excoriation, spreading of the wound, tissuenecrosis, irritation and hyperkeratosis.
 14. (canceled)
 15. A method oftreating skin-derived or tissue-derived pain in a human or non-humanmammal, by applying to the painful area as a topical dressing a hydrogelcomposition, wherein the hydrogel composition comprises: (i) ahydrophilic co-polymer carrying multiple pendant anionic groups, whereinthe polymer is derived from a first monomer and a second monomer,wherein both monomers have an octanol:water partition coefficient Log Pvalue of less than 0, wherein the first monomer has a Log P valuegreater (more positive) than the second monomer and the weight ratio(w/w) of the first monomer/second monomer in the hydrogel composition isequal to or more than about 1; or (ii) a hydrophilic copolymer formedfrom a first monomer and a second monomer, wherein the first monomercomprises an acrylic acid ester sulphonic acid monomer or salt thereof,and the second monomer comprises an acrylamide sulphonic acid monomer orsalt thereof, the weight ratio (w/w) of the first monomer/second monomerin the hydrogel is equal to or more than about 1 and, either (i) thesulphonic group in both first and second monomers is in acidic form or(ii) the sulphonic group in both first and second monomers is in saltform and the counterion for both monomers is the same.
 16. (canceled)17. A method of inhibiting inflammation and/or the complement cascadeand/or the kinin cascade, in a human or non-human animal patient,comprising contacting an affected location of the patient's body for aneffective period of time with a hydrogel composition, wherein thehydrogel composition comprises: (i) a hydrophilic co-polymer carryingmultiple pendant anionic groups, wherein the polymer is derived from afirst monomer and a second monomer, wherein both monomers have anoctanol:water partition coefficient Log P value of less than 0, whereinthe first monomer has a Log P value greater (more positive) than thesecond monomer and the weight ratio (w/w) of the first monomer/secondmonomer in the hydrogel composition is equal to or more than about 1; or(ii) a hydrophilic copolymer formed from a first monomer and a secondmonomer, wherein the first monomer comprises an acrylic acid estersulphonic acid monomer or salt thereof, and the second monomer comprisesan acrylamide sulphonic acid monomer or salt thereof, the weight ratio(w/w) of the first monomer/second monomer in the hydrogel is equal to ormore than about 1 and, either (i) the sulphonic group in both first andsecond monomers is in acidic form or (ii) the sulphonic group in bothfirst and second monomers is in salt form and the counterion for bothmonomers is the same.
 18. (canceled)
 19. The method of claim 12, whereinwound is a chronic skin lesion.
 20. The method of claim 17, wherein theinflammation and/or the complement cascade and/or the kinin cascade is achronic skin lesion.